Sulfonylurea derivatives



June 9 1964 Tsu'roMU IRIKURA ETAL 3,136,814

SULFONYLUREA DERIVATIVES Filed Sept. l2, 1962 United States Patent O 3,136,814 SULFNYLUREA DERWATIVES Tsutomu Irikura, 72 Shimura-Nakadaimachi, Itahashi-ku; Seigo Snzue, 32 3-eiiome, Ultima, Kita-ku; and Yasno Abe, 122 1-cholne, finden, Shibuya-ku, ali of Tokyo,

Japan Filed Sept. 12, 1962, Ser. No. 223,024 Claims priority, application Japan Apr. 7, 1962 3 Ciaims. (Cl. 260-553) The present invention relates to novel sulfonylurea derivatives or salts thereof which are useful for the hypoglycemic action they can exert. These derivatives are represented by the following general formula:

in which X stands for a halogen atom and Z means a cyclic radical the derivatives of the present invention will hereinafter be indicated as a series of compounds representable by the formula can be synthesized in accordance with the following schemes: For the compounds of Series I wherein Z represents a bicyclic radical` The compounds of Series I can be prepared by making a sulfonamide of the corresponding type as a salt of alkali, for example, sodium salt or potassium salt thereof in the presence of an appropriate solvent such as water, acetone or aqueous acetone react of an isocyanate of the corresponding type, namely, bicyclo (2,2,2) octane-2- isocyanate or A-bi'cyclo (2,2,2) octene-Z-isocyanate at a temperature between C. and the boiling point of the specific solvent employed. c

As a matter of fact, such compounds as represented by the above-presented general formula or the Formula I have not yet been reported in literature, their physiological activity being of course yet unknown. The inventors concerned, examining by using rats as test animal the hypoglycemic action of the compounds they prepared in accordance with the above-explained procedures and indeed in comparison with the known-preparations of tolubutamide, namely, N-ptoluenesulfonyl-Nbutyl urea and of chloropropamide, namely, N-p-chlorobenzeneice Explaining the screening practiced among various ltypes of compounds in their aspect of hypoglycemic activity, the experiment concerned was carried out as follows:

Test animal rat individuals having abstained from food for 24 hours were internally dosed each withy a specified kind of test compound of 300 mg./kg. Blood sugar was determined at the times of 1, 2, 4, 6 and 24 hours after the dose While the rats were fed after the lapse of first 6 hours to facilitate the yblood sugar value to be restored. The drop in blood sugar value was always estimated as mg. percent in' reference to the blood sugar value for control which was appraised as 100. The values given herein are those averaged among 6 individuals of test rat.

In FIG. 1, the data showing hypoglycemictactivity are presented for two representatives of the compounds having the structure of Formula I, namely, N-p-chlorobenzenesulfonyl-Nf-bicyclo (2,2,2) octane-Z-urea and N- p-chlorobenzenesulfonyl-N'-A5-bicyclo (2,2,2) octene-Z- urea. These compounds may both be regarded as of ,better eiiiciacy not only in the strength of potency but .and restored their normal values of blood sugar first `after the lapse of 4S hours.

Now, several examples ofthe practice ofthe present invention will be given in the following.

EXAMPLE I N-p-ChloroberzzenesulfonyIN'-Bicyclo (2,Z,2)

Octane-Z-Urea In 20 cc. of acetone is dissolved 6 g.V of p-chlorobenzenesulfonamide, added with 1.3 g. of NaOH dissolved in 40 cc. of water and further added at 10 C. drop by drop with 4 g. of bicyclo (2,2,2) octane-Z-isocyanate. After stirring for 3 hours at room temperature, the reaction mixture s added with 100 cc. Water, acidified by addition of 30% sulfuric acid so that precipitation of crystals takes place. The crystals are separated by ltration, brought to solution by treating with 5% sodium carbonate solution. The filtrate of the solution obtained as freed from insoluble matters is acidiiied to cause separation of crystals. The crystals arev collected and recrystallized from a mixture of methanol and actonitrile (1:1), polyhedral, colorless crystals being obtained which has a melting point of 218 C.

IR absorption spectrum: N H, 3360 and 2960 cm; PC O, CHL-1; 1/N H (amide cHLwl; 11N-H (amide III), 1450 cm; vs o, 1350 and 1165'cm.1; C H (p-sulbs'tituted phenyi), 835 and 765 cm; 5CH, -6cm.-1. l

EXAMPLE 2 N p Chloro!)enzeneszzlfonyl-Ni-A-Bicyclo(2,2,2)0ct tene-Z-Urea A reaction mixture comprising 6 g. of p-chlorobenzenesulfonylamide, 2O cc. acetone, 40 cc. aqueous sodium hydroxide containing 1.3 g. NaOH and 4 g. l5-bicycle (2,2,2) octene-Z-isocyanate is treated in the same way as in Example 1. After recrystallizing the product from a mixture of methanol and acetonitrile (1:1), there is obtained 5.3 g. of polyhedral, colorless crystals of which melting point is 224-6" C.

IR absorption spectrum: z/N H, 3360 and 2960 cml; we o, 1658 crnrl; N H (amide Il), `1540" cm; 1/N H (amide III), 1450 cm'; vs o, 1350 cm.1 and 1165 cml; 6C H (p-substituted phenyl), 835 and 765 cm.1; 6C H, 1158 cm.-1 (characteristic), C H, 1035 cm, 956 cm.1 and S46 cm.1 (shifted). v

L.; EXAMPLE 3 In 50 cc. of benzene is dissolved 13 g. of p-chlorobenzenesulfonyl carbamic ethylester and added with 4.3 g. of N-amino-pyrrolidine. After heating the reaction mixture on a Water bath for 30 minutes, the benzene is removed by evaporation. The residue is heated for 3 hours under a reduced pressure at 110-125 C. and then recrystallized from methanol, 6.5 g. of colorless crystals (M.P. 201 C.) being obtained.

IR absorption spectrum: N H, 3240 cm.-1 and 3120 CHL-1; 1/C O, Cm. 1; VCZQ, CUL-1; L'S,O, CHL-1, 1175 cin-1 and 1165 cml, 11S S02, 1100 cm; C H, CHL-1; C H, CHL-1; VC C1, CHL-l; 6N H, 760 cml.

EXAMPLE 4 N -p-C zlorobenzenesul folly l-N '-M orphol no- Urea In 120 ce. of benzene, 26 g. of p-chlorobenzenesulfonyl carbamic ethylester is dissolved and added with 10 g. of N-aminomorpholine, a homogeneous solution being produced under a weak evolution of heat. After recovering the benzene by treating the reaction mixture under a reduced pressure, the remaining content of the reaction vessel is heated for 4 hours at 110-130" C. After cool-` ing, 25.5 g. colorless crystals is obtained by recrystallization from ethanol, the compound aimed at being thus prepared as a specimen of which melting point is 206-208" C.

IR absorption spectrum: 1/N H, 3290 cnn-1 and 3120 cml; v 0, 1705 cm; 110:0, 1420 cm; vs o, 1350 cmrl; 1135502, 1280 cmi-1; 0 0, 1176 ern-1 and 1162 cm; 60 H, 1005 cm; 0 H, 900 cmrl; 1/0-01, 840 cm; N H, 760 cm.

EXAMPLE 5 N -p-Chlorobenzenesulfonyl-N '-3,5 -Dz'methyl Morpholino-Urea EXAMPLE 6 N -p-C/z loro benzenesul fony Z-N '-F perz'd l10- Urea A mixture consisting of 5 g. N-aminopiperidine, 13 g. of p-chlorobenzenesulfonyl carbamic ethylester and 50 cc. of benzene is treated in the same Way as in Example 4. On recrystallizing from methanol, there is obtained 8.3 g. of colorless crystals of the compound aimed at which has a melting point of 206-209 C.

IR absorption spectrum: 11NH, 3260 cm1 and 3120 cnr-1; 1/0 0, 1710 cml, 6N H, 1580 cml; 110:0, 1430 cml; v0 0, 11355 cm.-1 11805502, 1290 cmrl; vs o, 1178 (3111."1 and CHL-1; IIS S02, CUL-1; C H, cm.n1 and 986 cml; 0 H, 900 cm.1 1/0 01, 850 cml, NH, 760 cm.1.

EXAMPLE 7 N -p-Chlorobenzelzesul folly l-N '-Hexalz ydroazepno- Urea With 9.8 g. of potassium salt of p-chlorobenzenesulfonylamide (0.043 mol) is thoroughly mixed 8 g. of ethylhexahydroazepno-carbamate (0.043 mol). The mixture is then heated for 4 hours at 130-140" C. on an oil bath. By rccrystallizing the reaction product from a mixed solution made of diethyleneglycol dimethylether and dimethylformamide (1:3), there is obtained 4 g. of somewhat rened product melting at 176-179 C. After three times repetition of recrystallization, a product of high purity is Obtained of which melting point is 205 C.

As C13H18N3O3S Cl, calculated value: N, 12.67%. Analytical value: N, 12.90%.

EXAMPLE 8 N -p -C h lorobenzenesul fony l-N '-H exa/1 yd roazepno-U rea Into 250 cc. of beinzene, 26 g. (0.228 mol) o1' l-aminohexahydroazepine and 60 g. (0.228 rnol) of ethyl-pchlorobenzenesulfonyl carbamate are brought. The mix-, ture is then heated for 30 minutes under rellux on a water bath until there takes place a complete dissolution. Immediately thereafter, the benzene is evaporated ofr", and the residue is heated on an oil bath for 4 hours at 130- C. under a reduced pressure. By recrystallizing the content of the reaction vessel three times in the same way as in Example 7, the compound aimed at is obtained as a preparation having a melting point of 205 C., the yield amounting to 29 g.

IR absorption spectrum: 11N H, 3200 cm.1 and 3100 cml; 110,0, 1710 cml; 5N H, 1590 cm; 110:0, 1440 cm.-1; 0 0, 1360 cml; was S02, 1300 cml; vs o, 1180 cm.1 and 1170 cml; 11S S02, 1100 cml; 0 H, 1020 cm.1 and 990 cml; 50 H, 900 cml; 110 01, 840 cnr-1; N H, 765 cm.1.

Having thus described the invention, what is claimed as new and desired to be secured by Letters Patent is:

1. A sulfonylurea derivative of the formula:

in which X is halogen and Z is selected from the group consisting of 2. N-(p-chlorobenzenesulfonyl) N bicyclo (2,2,2) octane 2-urea.

3. N-(p-chlorobenzenesulfonyl)NA5 bicyclo (2,2,2) octene-Z-urea.

References Cited in the tile of this patent UNITED STATES PATENTS OTHER REFERENCES Marshall et al.: J. Org. Chem., vol. 23, pp. 927-929 (1958), QD 24116.

French Patent Abstracts, vol. 2, No. 26, Group 3, page 3 (June 1962). 

1. A SULFONYLUREA DERIVATIVE OF THE FORMULA: 